Treating degenerative dementia with low intensity focused ultrasound pulsation (lifup) device

ABSTRACT

Ultrasonic energy is used for treating degenerative dementia. A focal point of an ultrasonic transducer beam is directed at a target area of the brain to promote removal of substances that accumulate in the interstitial pathways that are at least partially responsible for the degenerative dementia. In one example, the target area of the brain may comprise the hippocampus and the degenerative dementia may be Alzheimer&#39;s disease. The ultrasonic beam may stimulate brain tissue at a frequency that corresponds to a naturally occurring deep sleep burst frequency of neurons and subsequent astrocyte activation patterns that drive a convective process responsible for brain solute disposal. For example, the transducer may generate a burst frequency of between 1-4 hertz to stimulate deep sleep brain functions that help remove amyloid plaque.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application claims priority to Provisional PatentApplication Ser. No. 62/434,744 filed Dec. 15, 2016, entitled TREATINGDEGENERATIVE DEMENTIA USING LOW INTENSITY FOCUSED ULTRASOUND PULSATION(LIFUP) DEVICE, which is incorporated by reference in its entirety.

The present application is also a continuation-in-part of U.S. patentapplication Ser. No. 15/382,351 filed Dec. 16, 2016, entitled:STEREOTACTIC FRAME which is incorporated by reference in its entirety.

The present application is also a continuation-in-part of U.S. patentapplication Ser. No. 15/456,266, filed Mar. 10, 2017, entitled: FOCUSEDULTRASONIC TRANSDUCER NAVIGATION SYSTEM, which is a divisional patentapplication of U.S. Pat. No. 9,630,029 filed on Sep. 5, 2014, entitled:FOCUSED ULTRASONIC TRANSDUCER NAVIGATION SYSTEM which is a divisionalpatent application of U.S. Pat. No. 9,061,133 filed Dec. 27, 2012 whichare all herein incorporated by reference in their entireties.

COPYRIGHT NOTICE

A portion of the disclosure of this patent document contains materialwhich is subject to copyright protection. The copyright owner has noobjection to the facsimile reproduction by anyone of the patent documentor the patent disclosure, as it appears in the United States Patent andTrademark Office patent file or records, but otherwise reserves allcopyright rights whatsoever.

TECHNICAL FIELD

The technology relates to treating degenerative dementia using lowintensity focused ultrasound pulsation (LIFUP).

BACKGROUND

Ultrasonic energy is used to treat different medical conditions. Duringtreatment, transducers apply ultrasonic energy to a treatment zone or“target” within a patient. For example, the ultrasonic energy may beapplied to a clot to dissolve or remove a blockage within the brain. Ofcourse other types of disorders also may be treated with ultrasonicenergy. For example, ultrasonic therapy may be used for treating otherpsychiatric, neurological, and medical disorders.

Ultrasonic therapy may apply ultrasonic energy to the same treatmentzone over multiple treatment sessions. Each treatment session may needto apply the ultrasonic accurately and repeatedly to the same treatmentzone. A Magnetic Resonance Imaging (MRI) machine may first scan thebrain, or other body part, to locate the target area. The ultrasonicsystem is then adjusted to focus the ultrasonic energy onto the locatedtarget area. Ultrasonic therapy may be time consuming and expensivesince each session requires a trip to a hospital and use of a MRImachine to relocate the same target area.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A is a focused ultrasonic transducer navigation system used fortreating degenerative dementia.

FIG. 1B shows the transducer system targeted at the hippocampalformation and entorhinal cortex.

FIG. 1C shows the transducer system targeted at a prefrontal brainregion.

FIG. 1D shows the transducer system targeted at a parietal temporaljunction.

FIGS. 1E and 1F show example pulse waves used by the transducer systemfor treating degenerative dementia.

FIG. 1G is a perspective view of a focused ultrasonic transducernavigation system used for treating degenerative dementia.

FIG. 1H is a side view of straps used for attaching the ultrasonictransducer navigation system to a patient.

FIG. 2 is a side view of the ultrasonic transducer navigation system.

FIG. 3 is a partial side sectional view of a top adjustment assembly.

FIG. 4 is a front sectional view of the ultrasonic transducer navigationsystem.

FIG. 5 is a side view of a template used for aligning the ultrasonictransducer navigation system.

FIG. 6 shows reference marks created using the template of FIG. 5.

FIG. 7 is a side view of the ultrasonic transducer navigation systemattached to a patient.

FIG. 8 is a front sectional view of the ultrasonic transducer navigationsystem shown in a lowered position.

FIG. 9 is a front sectional view of the ultrasonic transducer navigationsystem shown in a raised position.

FIG. 10 is a front view of another version of a transducer system usedfor treating degenerative dementia.

FIG. 11 is another front view of the transducer system shown in FIG. 10.

FIG. 12 is a side view of the transducer system shown in FIG. 10

FIG. 13 shows a computer system used for controlling the ultrasonictransducer navigation system.

DETAILED DESCRIPTION

A transducer system uses low intensity focused ultrasound pulsation(LIFUP) in a unique way to remove substances that may accumulate in theinterstitial spaces of the brain that are believed to be at leastpartially responsible for degenerative dementia, including Alzheimer'sdisease, Parkinson's dementia, frontal lobe dementia, and otherdegenerative processes.

One symptom of degenerative dementia is a lack of deep sleep. Deep sleepmay promote the removal of toxic byproducts that develop in theinterstitial spaces of the brain during awake states. During deep sleep,the interstitial spaces may open up. Astrocyte cells within the braininclude fingers that may produce a convective force that moves fluidalong the interstitial spaces flushing out amyloid precursor proteinsthat may turn into plaque if not swept out.

The finger like astrocyte projections providing the plaque removingconvection forces appear to be excited by neurons that activate at arate of around once per second. In other words, electrical waves ofaround 1-4 cycles per second produced by the brain during deep sleep maystimulate the astrocyte cell fingers and help prevent amyloid plaquebuildup that contributes to degenerative dementia.

The transducer system may generate ultrasonic waves at the same 1-4Hertz cycles normally produced during deep sleep helping to open upinterstitial spaces and stimulate the astrocyte cells that may flushdementia causing amyloid plaque from the brain.

The present ultrasound device and procedure uses focused and pulsatileultrasound that targets and optimally stimulates brain tissue at afrequency that corresponds to the naturally occurring burst frequency ofneurons and subsequent astrocyte activation patterns that appear todrive the convective process responsible for brain solute disposal. Theultrasonic treatment may be applied during natural or sedated sleep tooptimize solute removal with sonolysis caused by the interstitial spacesopening and improved glymphatic flow during sleep.

An ultrasonic probe is initially targeted using anatomical MRI imagesand optionally with co-registered functional images with brain siteaiming based on an individual's surface fiducials which have beencorrelated with imaging surface landmarks. Scalp location and angulationsettings for the probe use standard surface measurement techniques as instandard electroencephalogram (EEG) placement techniques or optionallyusing MRI based optical tracking equipment. While in an MRI scanner,targeting is confirmed using Arterial spin labeling activation patternsor optionally another blood oxygen level dependent (BOLD) protocol.

The ultrasonic therapy may be applied during a patient sleep state foroptimum opening up of the interstitial spaces of the brain. In oneexample, sedation is obtained using dexmedetomidine or other agentsdesigned to block norepiphrine. Blocking norepinephrine innervation mayshrink astrocytes which further open the interstitial pathways.

In one example, the pulse frequency will be at 1-4 Hertz to correspondwith the naturally occurring predominant brain rhythms of the sleepstate. Maximum power settings will be utilized as set forth by Food andDrug Administration (FDA) regulations. One example therapy may include30-90 minute treatments twice per week and may continue until thepatient demonstrates stabilization or improvement of repeatablecognitive measures including, but not limited to, resting brain networks(RBNS) and Montreal cognitive assessment (MOCA). Plaque removal can befollowed with position emission tomography (PET) scans and lumbarpuncture cerebral spinal fluid (CSF) sampling.

Site targeting within the brain may depend on which cognitive domain ismost affected for each patient. For example, the hippocampus through atemporal scalp window may be targeted for Alzheimer's disease withpredominant amnestic syndrome which primary affects the hippocampus. Thetransducer system may target other areas of the brain for otherdegenerative dementias. For example, the transducer system may focusultrasonic waves at a different area of the temporal lobe associatedwith language functions. In one example, a patient may show signs ofboth memory and language loss and ultrasonic waves may be applied toboth associated areas of the brain.

Transcranial Ultrasound Treatment of Degenerative Dementia

FIG. 1A shows a transducer navigation system (TNS) 100 used for treatingdegenerative dementia, such as Alzheimer's disease and otherneurodegenerative conditions characterized by extracellular deposits ofmaterial which are apparently toxic and which may accelerate additionaldeposit accretion by obstructing the flushing effects of interstitialflow.

FIG. 1B shows an axial section through the mesial temporal lobe and TNS100 targeted at the hippocampal formation and entorhinal cortex 34.Targets 34 are deep below the temporal ultrasound window in the 3.5 to 5cm range from the surface. TNS 100 may focus ultrasonic waves 30 ontarget 34 for patients with Alzheimer's disease or other degenerativeconditions with predominant memory loss symptoms (amnestic syndrome).These cases are characterized by amyloid deposits that disrupt themesial temporal structures.

FIG. 1C shows an axial section through a prefrontal region 42. Targets42 are shallower than in FIGS. 1A and 1B. Brodmann areas 46 and 9 appearto be associated with executive function. TNS 100 may focus ultrasoundwaves 30 at prefrontal targets in the 2.5 to 3.5 cm range for patientswith dysfunction predominantly affecting target area 42.

FIG. 1D shows an axial section through a parietal temporal junction areaassociated with patients with language disturbance associated withAlzheimer's disease (logopenic syndrome). TNS 100 may focus ultrasonicwaves 30 at target area 44 in the 2.5 to 3.5 cm range. Apraxic speechlocalization is more anterior in the frontal operculum. Likewise, morerostral and anterior localizations are used for patients withParkinson's that have predominant movement disorders including freezingand motor fluctuations (Brodmann area 6).

The description below may refer to treating Alzheimer's disease.However, it should be understood that the system and methods describedbelow may be used for treating any type of degenerative dementia or anyother disease associated with amyloid plaque.

As mentioned above, a significant amount of extracellular wasteresulting from brain activity appears to be removed by convectionthrough extracellular spaces extending along perivascular spaces intothe cerebrospinal fluid (CSF) space and outwards along lymphaticchannels. Numerous trials of agents designed for blocking the productionof amyloid plaque with enzymatic inhibitors or accelerating itsdestruction with antibodies have been unfruitful so far in reversingcognitive impairment although there has been modest slowing of cognitivedecline. The failure has been partly attributed to the potentialinability to break up the amyloid deposits with enough safety andprecision using systemic treatments.

TNS 100 uses a targeted approach for Alzheimer's disease usingtranscranial ultrasound. Optimal application of sonolysis leveragescertain aspects of brain physiology and the pathophysiology of brainfluid dynamics relating to Alzheimer's disease. One factor leveragedincludes the known lack of slow wave sleep in Alzheimer's patients andhow the inability to attain slow wave sleep constricts the flow ofinterstitial fluid.

Ultrasonic waves 30 applied by TNS 100 to target areas of brain 20 mayfoster or simulate slow wave sleep physiology on demand and may reopenpathways for the reestablishment of interstitial fluid convection. TNS100 optimizes the delivery of ultrasonic energy 30 in a safe andtargeted fashion in order to directly break up plaque or to stimulatecellular elements in order to accentuate convective effects in regionalareas of interest such as the hippocampus 34, parahippocampal gyrus 36,and other target areas 42 and 44 shown in FIGS. 1C and 1D, respectively.

Slow wave sleep is characterized by one to four Hertz slow waves withscalp EEG recordings and is a state of little observable muscle activityand a reduced ability to arouse. Microelectrode recordings demonstratebursts of high frequency neuronal firing interspersed with quiet periodsrecurring at a frequency of one Hertz.

The neuronal bursts release glutamate which induces movements inastrocyte filopodia. The later may contribute on some level toconvection forces or shaping the interstitial spaces. EEG surface wavesoccur in a coherent fashion with a phase lag from frontal to occipitallobe under some conditions but with selective stimulation the day beforesleep recordings, the waves can be made to emanate from the site ofstimulation outwards. In other words, the wave initiation site reflectstargeted stimulation the day before.

If slow waves have a purpose, this functional relationship may beexplained by one of two considerations. Either the slow wave initiationreflects a process which is related to memory consolidation, a processthat experimentally has been related to slow wave sleep, or, the slowwave initiation site is related to increased need to dispose of activityinduced toxic byproducts that would otherwise interfere with learningconsolidation.

The latter explanation seems possible since there is a knownrelationship between lack of slow wave sleep in Alzheimer's diseasewhich is characterized by deposits of amyloid that appear to result fromprocessing of amyloid precursor protein (APP) which is stimulated bysynaptic activation.

In deep sleep, the locus coeruleus is relatively inactive. Theconsequential reduction in norepinephrine input to astrocytes may leadto cell shrinkage and resultant opening of interstitial spaces thatshould promote convective effects. Notably, locus coeruleus degenerationis a very early event in Alzheimer's disease. However, levels ofcerebral norepinephrine, transporter function and receptor densities maybe maintained or increased so that any direct potential effect of locuscoeruleus neuronal loss is uncertain.

Perhaps of greater significance is the loss of lateral hypothalamicneurons in Alzheimer's disease that are used for triggering deep sleep.The direct effects of not triggering deep sleep and the indirect effectsof consequential failure to inhibit residual locus coeruleus functionmay prevent the coordinated astrocyte morphing required for facilitatinginterstitial convection.

Correcting conditions that interfere with deep sleep such as sleep apneaand adopting treatment regimens that promote healthier sleeparchitecture would be strategically sound. How to promote deep sleep ondemand may require certain medications. Acutely, anesthetic agents donot simulate normal sleep closely; however, a sedated statecharacterized by slow waves, along with inhibition of norepinephrine,can be created with short acting agents such as dexmedetomidine.

Prior to applying ultrasonic energy 30 to brain 20, the interstitialspaces are opened up as in slow wave sleep with a norepinephrine blockersuch as dexmedetomidine. Then targeted ultrasonic waves 30 are appliedto brain 20 to facilitate plaque removal in patients with degenerativedementia, including Alzheimer's disease.

Although there has been some concern about anesthesia as a potentialrisk factor for dementia, dexmedetomidine has a good safety profile whenused in elderly and acutely ill patients. Alternatively, sleepdeprivation or withdrawal from armodafinil or other stimulants may beused to induce sleep during ultrasonic wave therapy. The above sleepcondition may cause the interstitial pathways to sufficiently open toallow for egress of extracellular waste including amyloid plaque.

Ultrasonic energy 30 from TNS 100 solubilizes, mobilizes and potentiallyfacilitates convective forces. Immune therapy aimed at plaque has beenineffective or minimally effective in promoting an effective dissolutionprocess although there is evidence of partial plaque dissolution andmobilization based on increased levels of amyloid related proteinABeta42 found in post treatment CSF and peripheral blood samples.

TNS 100 treats amyloid plaque by causing the deformation of acousticwaves by the skull as well as accurately targeting tissue at risk forAlzheimer's disease. For example, TNS 100 can be used for human clotlysis and targeting the hippocampus 34, parahippocampal gyms 36, andmesial temporal lobe which are the commonly affected structures inpatients with Alzheimer's disease.

To prevent skull 22 from impeding ultrasound waves 30, TNS 100 may use atemporal window 40 (FIG. 1A) which is a thin region of the skull thatusually allows for successful insonation. However, TNS 100 may beattached to any location on skull 22, such as on the middle of theforehead for target areas in thedorsolateral prefrontal cortex.

Ultrasonic targeting by TNS 100 also may use Doppler imaging fromcommercially available units to identify the posterior cerebral arterythat fortuitously runs just medial to the hippocampal formation 36 andthen clamping TNS 100 in a targeted position as described below.

TNS 100 may use other types of advanced targeting and greater targetselection that combines multiple ultrasound sources in a spherical arrayand uses acoustic wave correction for skull distortion and thermalimaging with MRI for high intensity focused ultrasound.

TNS 100 may include a stereotactic head holder device so treatmentsessions may proceed outside of the MRI scanner once initial targetinghas been performed. Hybrid systems may use multiple detectors throughthe temporal window without the use of a spherical array.

Mechanical and heating effects may be applied for direct dissolution andmobilization of amyloid plaque. However, the ability of transcranialultrasound to stimulate neuronal discharge may facilitate convectiveforces by the release of glutamate and the subsequent activation ofastrocyte filopodia. With the latter in mind, TNS 100 may use 1-4 Hertzpulse rates in order to be coherent with natural burst rates of neuronsduring slow wave sleep.

Simulating Deep Sleep With Ultrasonic Pulsing

FIGS. 1E and 1F show example ultrasonic pulses generated by TNS 100. Asexplained above, TNS 100 may generate ultrasonic pulses 50 at a rate oraround 1-4 Hertz to simulate deep sleep brain functions that may helpremove amyloid plaque. For example, the period of pulses 50 may helpopen up interstitial spaces in the brain causing astrocyte cell fingersto produce convective forces that help breakup and remove amyloidplaque. The heat produced by pulses 50 on the target areas then furtherbreak up the amyloid plaque that is then removed by the astrocyte cellfingers.

In one example, pulse trains 54 are generated at 1-4 Hertz (1000milliseconds (ms)-250 ms). Pulse trains 54 may include separate groups52 of pulses 50, such as a series of 5 pulses 50 with a duration of0.2-5 milliseconds (ms), a period of 10 ms, and a combined duration of50 ms. Other pulse trains 54 may use more or fewer groups 52 of pulses50 at longer or shorter durations and periods. For example, pulse train54 may include single pulses 50 each with a duration of 50 ms and aperiod of 1-4 Hertz. Pulses 50 represent an on state of TNS 100. Duringthe on state, the transducer in TNS 100 may generate any combination ofsinusoidal ultrasonic waves know in the art.

The duration and number of pulses 50 may vary depending on the type oftransducer and ultrasonic power output by the transducer. For example, alarger diameter transducer may create a more conical ultrasonic beamthat produces higher temperatures. Ultrasonic waves 30 are pulsated tocreate a temporary rise in brain temperature at the target locationwithout creating lesions, thermal ablation of neural tissue, or anyother permanent change in brain structure. Longer duration pulses 50 maycreate more thermal deposition. The 10 ms period in pulse groups 52allow brain tissue to rest between each individual pulse 50 while the1-4 Hz period between pulse groups 52 stimulate deep sleep brainfunctions, such as the opening up of interstitial spaces in the brainand the activation of astrocyte cell fingers that produce convectiveforces.

In one example, pulses 50 may create an intensity spatial peak temporalaverage (ISPTA) of around 650-10,000 mwatts/cm². A typical treatmentsession may apply ultrasonic pulses 50 to a target area for around 30-90minutes to simulate a complete deep sleep period.

Extensive research into the heating of tissue from ultrasound exposurehas led to the development of several guideline relationships thatdescribe the safe exposure duration for a given temperature increase.Specifically, for temperature increases of 6° C. or less (which is thetemperature at which non-reversible tissue changes occur) the followingrelationship has been derived for non-fetal tissue:

ΔT<6−(log t)/0.6

where ΔT is the maximum expected temperature rise above normal bodytemperature (37° C.), and t is the duration in minutes that the exposurecan be maintained without incurring damage.

From this relationship, and the ultrasound parameters used for LIFUP,the safe exposure time can be estimated. In use, the LIFUP systemcreates temperature rises within the brain of less than 0.5° C., whichis the lower limit of the MRI thermography techniques used.Conservatively, if ΔT is set to 0.5, solving for t yields an exposuretime over 16 hours. Thus, unlike other ultrasound systems which are usedto produce thermal lesions within the brain tissue, for instance, totreat Parkinson's disease, the LIFUP system disclosed herein can beconsidered safe over extended treatment times.

While the current embodiments show a single transducer on one side ofthe head, positioned at the so-called temporal window, there are othertransducer configurations which can provide advantages in certainsituations. For instance, positioning the transducers bilaterally oneither side of the skull affords the possibility of using one of thetransducers as a receiver while the other is a transmitter. In this way,the conduction of the ultrasound energy into the skull can beindependently ascertained, without the need for MRI verification. One ofthe transducers can specifically be designed as a receiver, or bothtransducers can be identical in design, since piezoelectric transducersare reciprocal in nature. The advantage of a specifically designedreceiver is that it could, for instance, be unfocussed, so that it has abroader range of coverage within the skull. An advantage of thisbilateral approach is that it could be used to verify transmissionwithout the use of an MRI system.

EXAMPLE PROCEDURE

One example process applies transcranial ultrasound treatment fromultrasonic waves 30 generated by TNS 100 to treat mild cognitiveimpairment (MCI) or dementia. In one example, patients showed cognitivedecline with mild cognitive impairment (Clinical Dementia Rating stage0.5) through moderate dementia CDR stages 1 and 2.

In one example, patients are given a lumbar puncture for ABeta 42 andTau proteins for Alzheimer's Spectrum. The lumbar puncture is performedonce at entry. Patients were given an advanced MRI of the brain toinclude volume measurement of the hippocampus, ASL perfusion scans andMRS of prefrontal, precuneus, and hippocampus.

On entry, patients may have CDR stage of at least 0.5 and at least oneabnormal imaging biomarker. Baseline, two months (completion) testingmay include the Quick Dementia Rating System (QDRS) for staging and thefollowing battery of tests:

-   -   the Repeatable Battery for Assessment of Neuropsychological        Status (RBANS),    -   Standardized 25 foot timed gait test    -   the Nine Hole Pegboard Test,    -   Montreal Cognitive Assessment Test versions 1,2,3 (MOCA),    -   Brain imaging will be repeated at completion that include an        anatomical scan (MPRAGE), ASL and BOLD and MRS in the targeted        network.

CSF studies demonstrated good sensitivity and specificity for MCI anddementia of the Alzheimer's type (ref 5). MRI volumetrics, perfusionscans and MR spectroscopy have shown to be good discriminating valueamong AD, PDD/DLB and FTLD subgroups and is responsive to change aspatient's progress from MCI to dementia.

For patients with amnestic predominant cognitive change, TNS 100 istargeted at the mesial temporal lobe through a trans temporal scalpwindow. Targeting may include referencing scalp fiducials based on anobtained MRI. A Doppler waveform confirmation may be obtained because ofthe ability of transcranial Doppler (TCD) to record Doppler signals fromthe posterior cerebral artery that runs medial to the mesial temporallobe.

TNS 100 may target the temporal parietal region for LogopenicAlzheimer's. TNS 100 may target other regions for Parkinson's dependingon the clinical requirements. TNS 100 may target area 6 for severe motorsymptoms or the frontal lobe or mesial temporal lobe for dysexecutiveand amnestic syndromes, respectively.

Alzheimer ultrasonic procedures may place the patient in a quiet room ina post op area of a certified outpatient surgical center where medicalstaff with a limited EEG montage monitor eye movements, muscle tone,frontal and occipital EEG for tracking sleep stages. The media staffalso may monitor patient EKG and pulse oximetry.

Techniques used for promoting sleep in the office may include mild sleepdeprivation, holding off on stimulants, and potentially using sleepinducing medication. Slow wave sleep is targeted. TNS 100 applies 30-90minutes of ultrasound to the patient with a two megahertz probe affixedto the headset with parameters set within FDA safety limits fordiagnostic ultrasound. The patient is allowed to wake up after thetreatment session and may be discharged when fully awake and in the careof a responsible adult. In one example, ultrasonic energy is applied tothe patient for 30-90 minutes and is repeated once per week for aroundtwo months.

Regions of the brain where ultrasonic waves 30 are applied may depend onthe network target. For example with amnestic predominant Alzheimer'sdisease TNS 100 may direct waves 30 to a region of interest (ROI) on themesial temporal lobe and evaluate connectivity for output network nodessuch as the anterior nucleus of the thalamus and the precuneus. Forlogopenic forms of Alzheimer's, TNS 100 may direct waves 30 to thetemporal parietal region with a ROI in this region and connectivityanalysis of frontal-parietal connections.

Example Transducer Systems

FIG. 1G shows a perspective view for one example, ultrasonic TransducerNavigation System (TNS) 100. TNS 100 may be attached to a patient 88 andmay apply ultrasonic energy to precise target locations within patient88 associated with different types of degenerative dementia includingAlzheimer's disease. The explanation below discusses the specificexample of using TNS 100 to apply ultrasonic energy to a target locationwithin head 90 of patient 88 such as the hippocampus and/orparahippocampal gyms regions. However, it should be understood that TNS100 may apply any type of sonic, magnetic, or any other alternativeenergy to any target location within any body part of patient 88. TNS100 may be used on human patients or animal patients.

A housing assembly 102 comprises an outer housing 104 attached to amovable inner housing 106. A transducer (see FIG. 4) may be locatedwithin inner housing 106. A power cable 116 may attach to the transducerand extend up through inner housing 106 and outer housing 104. A firstvertical strap 108C attaches to elevating screws 114 and wraps aroundthe top of head 90 and underneath the chin of patient 88. A secondhorizontal strap 108 includes a ring shaped section 108A that attachesto an outside surface of outer housing 104 via screws 109A and nuts 109Band a headband section 108B that wraps around the front over the eyesand back of head 90. While shown attached to head 90, it should beunderstood that straps 108, or other attachment devices, may attachhousing assembly 102 to other body parts of patient 88. The housingassembly 102 may be attached by straps 108 to the right side or leftside of head 90 to apply ultrasonic energy to targets on inside eitherside of head 90.

Three housing arms 112 may extend radially out from sides of outerhousing 104. Elevating screws 114 may rotatably extend through housingarms 112 and may include elastomeric cushions 118 that press up againsthead 90. Elevating screws 114 may be rotated downward pressing againsthead 90 to reduce some of the compressive force of inner housing 106against head 90. This will be described in more detail below.

An alignment system 110 may move the transducer within inner housing 106into different x, y, and/or z positions with respect to head 90. The xposition may refer generally to front to back positions with respect tohead 90, the y position may refer generally to top to bottom positionswith respect to head 90, and the z position may refer generally to atransverse inside to outside, or left to right positions, with respectto head 90.

If TNS 100 were attached on the top of head 90, the x position may referto front to back positions with respect to head 90, the y position mayrefer to the left to right or side to side positions with respect tohead 90, and the z position may refer to the transverse inside tooutward or top to bottom positions with respect to head 90.

Alignment system 110 may comprise side adjustment assemblies 120 and atop adjustment assembly 140 that have the unique ability to move thetransducer within inner housing 106 in different x, y, and z directionswhile TNS 100 remains attached to head 90 of patient 88. This allowsmore precise alignment of the transducer with a target location withinhead 90. Alignment system 110 also may provide quicker and more accuratereattachment of the TNS to head 90 to a same relative position withrespect to the target location. This allows TNS 100 to be repeatedlyreattached during multiple ultrasonic therapy sessions without using aMRI device to relocate the target location.

Side adjustment assemblies 120 each include a side adjustment knob 122that rotatably attaches to a side extension 124 that extends radial outfrom the side of outer housing 104. Top adjustment assembly 140 includesa top adjustment knob 142 that is rotatably attached to outer housing104. A threaded ring 146 extends out through the middle of topadjustment knob 142. A top end 144 of a transducer lid extends outthrough threaded ring 146 and a cap 148 inserts into a center cavity ofthe top end 144 of the transducer lid. Cap 148 operates as a wire guidefor receiving cable 116 and also operates as a stop for top end 144 ofthe transducer lid.

FIG. 1H shows opposite ends 113 of strap sections 108B and 108C. In oneexample, a hook and eye type material 107, such as Velcro®, may beattached to the ends of strap 108. For example, ends 113 of straps 108may include a hook material and may be fed through cinches 111. Strapends 113 are pulled to hold housing assembly 102 snugly against theopposite side of head 90. The hook material on strap ends 113 is thenattached to eye material 107.

Other attachment assemblies may be used for attaching ends 113 of straps108. For example, hook and eye buckles or ratchet buckles may be used onends 113 of straps 108. In yet another example, strap sections 108B and108C may be formed from elastic materials that are stretched and heldcompressively over head 90. Of course other attachment devices also maybe used.

In one example, straps 108 may be made out of leather. However, anymaterial may be used that can securely hold housing assembly 102 againstpatient 88. As just discussed, straps 108 may alternatively be anelastic plastic, rubber, or cloth material. Straps 108 may be availablein multiple lengths and sizes to attach to various patient head sizesand patient body parts for small children to large adults.

FIG. 2 shows a side view of TNS 100. Outer housing 104 comprises acircular outside surface 160 with two openings 162 that show a portionof inner housing 106 attached to side adjustment assemblies 120. Housingarms 112 extend radially out from the sides of outer housing 104 andoperate similar to a tri-pod allowing TNS 100 to be steadily supportedby elevating screws 114 on varying elevational locations on head 90.

Side adjustment assemblies 120 may each include inner adjustment screws(see FIG. 4) that have first ends that attach to inner housing 106 andsecond ends that attach to side adjustment knobs 122. Two threadedstationary pins 164 are located on sides of outer housing 104 oppositeadjustment assemblies 120. Pins 164 slidingly insert into sides of innerhousing 106 opposite the sides attached to side adjustment assemblies120.

Side adjustment knobs 122 can be rotated in both clockwise andcounterclockwise directions. For example, rotating either one of sideadjustment knobs 122 in a clockwise direction may cause the inneradjustment screw to rotate inward. The inner adjustment screw in turnmoves inner housing 106 away from side adjustment assembly 120 andtoward an opposite end of outer housing 104 and toward one of pins 164.Rotating one of side adjustment knobs 122 also causes knob 122 to moveradially inward over an outside surface of side extension 124 and towardan outside perimeter 105 of outer housing 104.

Rotating any combination of side adjustment knobs 122 in an oppositecounter clockwise direction may cause the inner adjustment screws torotate outward. The inner adjustment screw in turn may pull innerhousing 106 toward side adjustment assembly 120 and away from theopposite end of outer housing 104 where pin 164 is located. The counterclockwise rotation also may cause side adjustment knob 122 to moveradially outward over the outside surface of side extension 124 awayfrom outside perimeter 105 of outer housing 104.

Gradations 126 are imprinted on the outside surface of side extensions124. In one example, each gradation 126 may be spaced apart onemillimeter (mm). Gradations 126 in combination with side adjustmentknobs 122 operate as micrometers identifying distances of x and ymovement of the transducer contained inside of inner housing 106. Forexample, after TNS 100 is attached to the head of the patient, sideadjustment knobs 122 may be rotated to adjust the location of thetransducer so a focal point of ultrasonic energy is directed preciselyover a target area inside of the brain of the patient.

Top adjustment knob 142 is co-centrically positioned on top of outerhousing 104. Threaded ring 146 is concentrically positioned within topadjustment knob 142 and cap 148 is concentrically positioned within topend 144 of the transducer lid and over threaded ring 146. Rotating topadjustment knob 142 in a first direction may move top end 144 of thetransducer lid in an upward z direction away from the head of thepatient. Rotating top adjustment knob 142 in a second opposite directionmay move top end 144 of the transducer lid in a downward z directiontoward the head of the patient.

FIG. 3 shows a partial side cut away view of top adjustment assembly140. Top adjustment knob 142 has an oppositely inclining top wall 145Aand an inner side wall 145B that form an inner hole 152 that receivesthreaded ring 146. Screws (not shown) may insert into side walls 145Band rigidly couple adjustment knob 142 to threaded ring 146.

Rotating top adjustment knob 142 in the first direction also rotatesthreaded ring 146 causing top end 144 of the transducer lid to move inan upward z-direction away from the head of the patient. Rotating topadjustment knob 142 in the second opposite direction also rotatesthreaded ring 146 in the same direction moving top end 144 of thetransducer lid in a downward z-direction toward the head of the patient.

Gradations 150 may be imprinted on an outside surface of top end 144 ofthe transducer lid. In one example, gradations 150 also have onemillimeter spacing. Gradations 150 in relation to the location ofrotating knob 142 also operate as a micrometer identifying an amount ofmovement of the transducer in the z direction.

FIG. 4 shows a front sectional view of TNS 100. Inner housing 106comprises a top wall 132, side walls 134, a membrane clamping ring 136,and a hypo-allergenic flexible membrane 138 that together form a sealedinner housing chamber 174 configured to retain a transducer assembly165. In one example, chamber 174 may be sealed and filled with degassedoil or water to improve efficiency of transferring the ultrasound wavesthrough the skull and brain and into the target location.

Membrane 138 may be formed of a plastic or rubber material and isconfigured to elastically press up against the head of the patient. Thethreaded connection of clamping ring 136 to side walls 134 allowmembrane 138 to be detached from the rest of inner housing 106. Acushion 137 may be glued to the bottom of clamping ring to increasecomfort and conform around irregularities on the surface of the head ofthe patient. After completing the ultrasonic therapy sessions for apatient, membrane 138 may be removed and replaced with a new membranefor a next patient. A layer of gel may be spread over an outside surfaceof elastic membrane 138 and may maintain a continuous seal betweenmembrane 138 and the head of the patient as will be discussed in moredetail below in FIG. 8.

Transducer assembly 165 comprises a transducer 166 located between atransducer lid 170 and a transducer base 178. A space between transducer166 and transducer lid 170 forms an airtight sealed back cavity 168. Aspace between transducer 166 and transducer base 178 forms a sealedfront cavity 176 configured to retain water. A single transducer 166 isshown in FIG. 4. However, inner housing 106 and transducer assembly 165may be configured to retain any transducer shape and any number oftransducers, such as circular transducers and multi-transducer arrays.

Transducer lid 170 includes a neck 172 that extends up inner housing106, outer housing 104, and threaded ring 146. As shown above, top end144 of transducer lid 170 extends up through a top end of threaded ring146 and includes a threaded internal hole 198 configured to threadedlyreceive cap 148. Left hand threads may be formed on the outside surfaceof cap 148 to prevent cap 148 from being unscrewed if it bottoms outagainst the top of ring 146. A threaded outside surface of neck 172 isconfigured to threadedly engage with a threaded inside surface of ring146. Cable 116 extends through a hole in the center of neck 172 andwires from cable 116 are coupled to transducer 166.

As mentioned above, rotation of top adjustment knob 142 in a firstdirection rotates threaded ring 146 around threaded neck 172 movingtransducer assembly 165 in a first upward z direction toward top wall132 of inner housing 106. Rotation of top adjustment knob 142 in theopposite direction rotates threaded ring 146 around threaded neck 172 inthe opposite direction moving transducer assembly 165 in a seconddownward z direction toward membrane 138. Cap 148 operates as a stoppreventing top end 144 of transducer lid 170 from moving down below atop end of threaded ring 146.

An O-ring 156 is located between threaded ring 146 and top end 144 oftransducer lid 170. An O-ring 158 is located between threaded ring 146and the inside surface of a hole formed in top wall 132 of inner housing106. O-rings 156 and 158 are configured to maintain a watertight or oiltight seal within chamber 174 while threaded ring 146 is rotated aroundtransducer neck 172. An O-ring 200 may be located between the bottom endof side walls 134 and membrane clamping ring 136 to provide a watertightor oil tight seal along the bottom end of cavity 174.

Inner housing 106 may be made of a clear see-thru plastic that allows atechnician to visually detect any air bubbles that may exist in the oilor water within chamber 174. Two compression nozzles 202 may be mountedwithin side walls 134 of inner housing 106. Compression nozzles 202 maybe used for filling chamber 174 with water or oil and bleeding airbubbles out of chamber 174, similar to bleeding air out of vehiclebraking systems. For example, water may be forced into a first one ofnozzles 202. A second one of nozzles 202 may be depressed or unscrewedto bleed water and air bubbles from chamber 174. An indication that mostor all of the air bubbles are removed may be provided when only waterbleeds out of second nozzle 202. Inner housing 106 may be shaken duringthe bleeding process to promote the air bubbles to exit out of secondnozzle 202.

Each side adjustment assembly 120 may include an inner adjustment screw128 that forms a head 190 at a front end and is attached to a sideadjustment knob 122 at a back end. A sleeve 194 is inserted into a holeformed in the side of inner housing 106. Screw head 190 inserts androtates inside of sleeve 194. An alignment guide 182 is attached toinner housing 106 and includes a lip 193 that seats into a groove 192formed in screw head 190. A sleeve 196 inserts into a hole formed in anouter opposite side of inner housing 106. A front end of threadedstationary pin 164 slidingly inserts into sleeve 196 and a back end ofpin 164 threaded and rigidly attaches to outer housing 104. An alignmentguide 184 attaches to inner housing 106 and slidingly presses against atop side of the front end of pin 164.

Threads are formed on an inside surface of a hole formed inside of eachside extension 124 and engage with threads on screw 128. Rotating sideadjustment knob 122 in a first direction rotates screw 128 and moveshead 190 in a forward direction. Screw head 190 pushes inner housing 106away from side extension 124 toward the opposite side of outer housing104 while sleeve 192 on the opposite end of inner housing 106 slidesfurther over the front end of pin 164.

Rotating side adjustment knob 122 and screw 128 in an opposite directionmove head 190 in a reverse direction. Head 190 pulls lip 193 andattached inner housing 106 toward side extension 124 while sleeve 196 onthe opposite side of inner housing 106 moves further out from the frontend of pin 164.

Alignment guides 182 and 184 allow inner housing 106 to move into any xand y position. For example, adjustment screws 128 may move innerhousing 106 into different positions. Alignment guides 182 may slideover groves 192 on screw heads 190 and alignment guides 184 may slideover pins 164 allowing movement of inner housing 106 into any x and yposition within outer housing 104.

Operation Overview

Referring to FIGS. 1-4, patient 88 may have focused ultrasonictransducer navigation system (TNS) 100 strapped onto head 90 whileundergoing an MRI-assisted positioning procedure. An administratorcontrolling an electronic power source stimulator may be in a nearbyroom which is safe from the magnetic field produced by the MRI device.The administrator may use a functional MRI (fMRI) method that showsimages from inside of the brain of patient 88 and shows a target spotspecific for treatment of a particular disorder.

TNS 100 may send a Low Intensity Focused Ultrasound Pulse (LIFUP) intothe brain which can be seen and recorded on an fMRI console screen as achange in a BOLD signal. The resulting location of the ultrasonic pulseis measured relative to the spot targeted for treatment. Alternatively,the location may be verified by fMRI sequences that measure smalltemperature changes within the brain occurring as a result of the LIFUPstimuli.

The administrator slides patient 88 out from under the MRI device andadjusts side adjustment knobs 122 and top adjustment knob 142(micrometer dials) to move the focus of the LIFUP generated bytransducer 166 to the desired target location. The MRI comparisonprocedure is repeated until transducer 166 generates an ultrasonic pulsedirectly on the center of the target location in all three x, y, and zplanes. TNS 100 is then used to perform an ultrasonic treatment.

A medically approved pen is used to mark a portion of a circle aroundthe perimeter of inner movable housing 106 and on the head of patient88. In one example, inner housing 106 may be made from a clear plasticmaterial. Marking the head with the ink pen enables subsequenttreatments to be administered in the office of a doctor or technicianwithout having to use an expensive MRI device to repeatedly realign TNS100. Thus the time and cost per treatment may be significantly reduced.

The three elevating screws 114 may be adjusted to any size and shape ofhead 90 and in one example may use comfortable STERalloy Elastomericcushions 118. Elevating screws 114 raise membrane 138 slightly off head90 to facilitate the free movement of inner moveable housing 106 in thex and y planes. Side adjustment assemblies 120 may be used to aligninner housing 106 with the circle previously marked on the head ofpatient 88 centering ultrasonic energy generated by transducer 166 intothe center of the target within the brain.

When the x and y planes are on target, elevating screws 114 are backedoff to lower membrane 138 more firmly against head 90. A gel may beapplied to membrane 138. The gel may maintain a contact layer betweenmembrane 138 and head 90 while membrane 138 is moved to different x andy positions. The gel layer may prevent an air gap from forming betweenmembrane 138 and head 90 that could reduce efficiency of the focusedultrasound waves output by transducer 166.

After completion of the LIFUP treatments, the STERalloy elastomericcushions 118, membrane clamping ring 136 and membrane 138 may bereplaced. This may prevent allergies or other undesirable effects frombeing transferred to other patients. The LIFUP procedure may be welcomedby the insurance companies as compared to surgery which may be moreexpensive and higher risk.

Initial Alignment and Treatment

During the initial MRI alignment procedure described above, the focalpoint of ultrasonic energy output from transducer 166 is aligned asclosely as possible to the center of the target location. This allowsmore tolerance when realigning TNS 100 during subsequent treatments.

Referring to FIGS. 5 and 6, patient 88 may lie on their side and head 90may be shaved in the installation location for TNS 100. A target mark210 is applied to head 90 with an ink pen 204. A template 202 includes ahole 208 that is aligned over target mark 210, holes 206 that arealigned with the outside perimeter of inner housing 106, and two slots212 that are aligned with one of housing arms 112. Template 202 may bemade from a clear semi-rigid plastic material.

Template 202 is placed against head 90 so hole 208 aligns over targetmark 210 and slots 212 are located in a desired location for one ofhousing arms 112. While holding template against head 90, ink pen 204 isused to apply reference lines 214 to head 90 through slots 212 and applyreference marks 216 to head 90 through holes 206. Template 202 is thenremoved. The third middle reference mark in each column of fivereference marks 216 is alternatively referred to as a center referencemark 216A.

FIG. 7 shows a side view of TSN 100 and FIGS. 8 and 9 show frontsectional views of TNS 100. FIGS. 7, 8, and 9 shows in more detail howinner housing 106 may be moved into different x, y, and z locations toalign with a target location 220.

The x, y and z planes in TNS 100 may be set to nominal positions bysetting side adjustment knobs 122 and top adjustment knob 142 each to 6mm. Gel may be applied to the entire surface of membrane 138 and may beapplied so it does not exceed a perimeter 218 of inner housing 106.Perimeter 218 may comprise the outside perimeter of membrane clampingring 136.

Elevating screws 114 are raised as shown in FIG. 8 so membrane 138contacts head 90. TNS 100 is aligned on head 90 so center referencemarks 216A for each column of five reference marks 216 align withperimeter 218 as shown in FIG. 7. Housing arm 112A is aligned betweenreference lines 214 as shown in FIG. 7. TNS 100 is held firmly againsthead 90 to prevent movement and the ends of straps 108 are tightenedholding TNS 100 firmly against head 90.

Patient 88 is placed under the MRI device. A pulse 222 from transducer166 is transmitted into head 90 of patient 88 using the stimulator. TheMRI device identifies the pulse location relative to target location 220in the x and y planes. If the pulse location is off more than 6 mm inthe x or y planes, TNS 100 may be removed from head 90 and the threecolumns of five reference marks 216 used as a guide to realign TNS 100.

For example, reference marks 216 in each column may be spaced a knowndistance apart. Perimeter 218 of inner housing 106 may be aligned nextto a different set of reference marks 216 based on the identifieddistance between the focal point of ultrasonic pulse 222 and targetlocation 220. Patient 88 then may be placed back under the MRI deviceand the distance re-measured between the new focal point for theultrasonic pulse 222 and target location 220. The realignment procedureis repeated until the distance between ultrasonic pulse 222 and targetlocation 220 is less than 6 mm in both the x and y planes.

If the x and y locations of ultrasonic pulse 222 are both within 6 mm oftarget location 220, elevating screws 114 are screwed down as shown inFIG. 9 to raise inner housing 106 slightly off of head 90. Sideadjustment knobs 122 shown in FIG. 7 then may move inner housing 106inside of outer housing 104. The x and y positions of inner housing 106are adjusted based on the previously measured distance between theultrasonic pulse 222 and target location 220.

For example, the MRI device may determine ultrasonic pulse 222 is spaceda distance of 2 mms from target location 220 in an x direction. One ofside adjustment knobs 122 may be used to move inner housing 106 2 mms inthe x direction. The three elevating screws 122 then may be retractedupward again as shown in FIG. 8 so membrane 138 presses firmly backagainst head 90. Another ultrasonic pulse 222 is applied to patient 88and the x and y position of the new pulse measured in relation to targetlocation 220.

The z plane position of inner housing 106 may be adjusted after the xand y positions of ultrasonic pulse 222 are aligned on target location220. For example, a distance of ultrasonic pulse 222 from targetlocation 220 in the z direction is measured from the MRI images. Topadjustment knob 142 is rotated to move transducer assembly 165 up ordown by the measured z distance. Head 90 of patient 88 is then rescannedby the MRI device and the new location of ultrasonic pulse 222 iscompared with target location 220. The measurement and adjustmentprocess is repeated until the focal point of ultrasonic pulse 222 alignsover target location 220 in the x, y, and z planes. After alignment ofultrasonic pulse 222, TNS 100 may be checked to see if any gel isvisible around perimeter 218 of inner housing 106. Any seeping gel maybe wiped clean with a swab.

FIG. 7 shows a pen 204 used for tracing a reference line on head 90around as much of perimeter 218 as possible. The z setting of TNS 100may be recorded on a patient identification card. For example, alocation of the top end of threaded ring 146 with respect to gradations150 on top end 144 of transducer lid 170 may serve as the z referencelocation (see FIG. 3). The reference line traced around perimeter 218 ofinner housing 106 may serve as the x and y reference locations.

An initial ultrasonic treatment then may be applied to patient 88 usingTNS 100. After completion of the treatment session, TNS 100 may be wipedclean and placed back into a case. The same TNS 100 may be reserved forall subsequent ultrasonic treatments for the same patient.

Subsequent Alignments and Treatments

Reference marks 216, reference line 214 shown in FIG. 6, and theaddition reference line drawn around perimeter 218 of inner housing 106on head 90, may be visually inspected. Any faded reference marks orlines may be redrawn on head 90.

TNS 100 is adjusted to nominal x and y positions by setting sideadjustment knobs 122 each to 6 mm. Gel is again applied to the entiresurface of membrane 138. Perimeter 218 of inner housing 106 isconcentrically aligned as closely as possible with the reference linethat was previously traced around perimeter 218. Housing arm 112 in FIG.7 is also aligned between the reference lines 214. Outer housing 104extends down about half an inch over inner housing 106, but still allowsviewing of outside perimeter 218 of inner housing 106.

TNS 100 is held firmly against head 90 to prevent it from moving whilestraps 108 is again wrapped and tightened around head 90. If necessary,elevating screws 122 are rotated down from the position shown in FIG. 8to the position shown in FIG. 9 to raise inner housing 106 enough toslide over head 90 without moving outer housing 104. As mentioned above,the gel on membrane 138 may maintain a contact layer between membrane139 and head 90 as inner housing 106 is being adjusted in the x and ypositions. The elevating screws reduce pressure of membrane 138 againsthead 90 of patient 88 and allow membrane 138 to remain in contactagainst head 90 while inner housing 106 is moved into different x and ypositions.

The x and/or y positions of inner housing 106 are adjusted untilperimeter 218 visually aligns with the circular marked line previouslytraced around perimeter 218 as shown in FIG. 7. Elevating screws 122 arerotated upward as shown in FIG. 8 until they no longer touch head 90.The z location of inner housing 106 is verified by comparing the zsetting on gradation 150 (FIG. 3) with the z setting on the patientidentification card. If necessary, top adjustment knob 142 may berotated to establish the previous z setting on gradation 150.

An ultrasonic treatment may now begin without having to realigntransducer 166 using an MRI device. When the ultrasonic treatment iscomplete, TNS 100 can be wiped clean and placed back into the originalcase for the next use by patient 88.

TNS 100 is designed to receive a variety of different transducers thatcan generate ultrasonic energy into the brain or other body parts at avariety of different depths to accommodate a variety of differentdisorders. For example, TNS 100 may be used for treating psychiatricdisorders, such as depression, anxiety, Obsessive-Compulsive Disorder(OCD), bulimia, bipolar disorder, or autism. TNS 100 also may be used totreat a variety of neurological disorders, such as epilepsy,Parkinson's, Alzheimer's, and other dementias, coma, and brain injury.TNS 100 also may be used to treat medical conditions, such as high andlow blood pressure, obesity, and endocrine and immunological disease;and perform functional diagnostics of brain circuits.

Alternative Transducer Navigation System

FIGS. 10-12 show an alternative transducer navigation system (TNS) 300also used for treating degenerative dementia. FIG. 10 is a front view ofTNS 300 with a transducer 308 pivoted at 10 degrees, FIG. 11 is a frontview of TNS 300 with transducer 308 pivoted at 15 degrees, and FIG. 12is a side view of TNS 300.

Another transducer navigation system also used for treating degenerativedementia is described in U.S. patent application Ser. No. 15,382,351filed Dec. 16, 2016, entitled: Stereotactic Frame which is incorporatedby reference in its entirety.

Referring to FIGS. 10-12, TNS 300 includes a top strap 302A and a bottomstrap 302B attaching to opposite upper and lower ends of transducercradle 304, respectively. A side strap 302C attaches at opposite ends toforward and rearward ends of cradle 304. Upper and lower straps 302A and320B may be attached at opposite ends via a ring 320.

A transducer casing 308 may retain an ultrasonic wave transducer 314 andhave rounded convex outer side walls 309 that fit inside of roundedconcave inner side walls 315 of cradle 304. The rounded walls 315 and309 allow transducer 314 to pivot at different angles 322 inside oftransducer cradle 304. In one example, pivot angle 322 can vary from 0to 15 degrees. However, pivot angle 322 can vary at a wider range ofangles depending on the size and diameter of cradle 304 and transducercasing 308.

An operator may loosen knob 324 and push the back of casing 308 to pivottransducer 314. Knob 324 is then tightened to hold transducer 314 at theselected pivot angle 322. A gel pack 306 may attach onto an inside faceof transducer cradle 304 and press against the side of head 90.Alternatively, gel pack 306 may attach to an inside surface oftransducer casing 308.

Cradle 304 and retained transducer 314 are attached via straps 302 to aparticular location on head 90 of patient 88 for treating a target areaassociated with degenerative dementia. A technician then may pivottransducer 314 within cradle 304 based on the location of focal point310 relative to the target area within the brain.

A first marking 316A on casing 308 may identify a 10 degree pivot angle322A and a second marking 316B may identify a 15 degree pivot angle322B. The technician may press one edge of casing 308 associated withone of markings 330. For example, the technician may press the edge ofcasing 308 at 30 degree marking 330 so an opposite side of casing 308 at150 degree marking 330 pivots to first marking 316A creating a 10 degreepivot angle 322A.

The patient 88 may be inserted into an MRI machine and transducer 314activated to detect the location of focal point 310A relative to thetarget area in head 90. Based on the location of focal point 310A, thetechnician may press down on another edge of casing 308 associated withanother marking 330 until an opposite side of casing 308 pivots tosecond marking 316B producing a 15 degree pivot angle 322B. For example,the technician may further pivot transducer 314 so focal point 310Bmoves into the hippocampus region 34 of the brain as shown above inFIGS. 1A and 1B. The technician then tightens screw 324 to lock casing308 inside of cradle 304.

If the new focal point 310B hits the target area, the technician recordsmarking 330 indicating the pressed edge of casing 308 and marking 316Bindicating the pivot angle 322 created at identified marking 330. Thetechnician then uses markings 330 and 316B to relocate focal point 310Bat the same target area for subsequent ultrasonic therapy sessions.

As mentioned above, transducer 314 may be located on the temporalwindow. However, other multi-array transducer devices and bi-lateraltransducer devices may be used for applying ultrasonic waves outside thetemporal window. Patient 88 may have several targets in the middletemporal lobe, including the hippocampus and surrounding cortex. Thetechnician may pivot transducer 314 into previously recorded pivotangles 322 for each of the different target areas.

TNS 300 can be operated within an MRI scanner and in one examplecontains no Ferro magnetic parts that would interfere with MRI magneticfields. In one example, TNS 300 may include only titanium and plasticparts.

TNS 300 may connect to a computer 340 that programs the pulse rates,pulse durations, and pulse train patterns described above in FIGS. 1Eand 1F. Computer 340 may store different ultrasonic pulse patterns fordifferent types of degenerative dementia and different target areas. Thetechnician may select the particular pulse pattern associated with theparticular dementia. Computer 340 then turns power to transducer 324 onand off to create the selected ultrasonic beam activation pattern.

Alternative Embodiments

The embodiments described above use a single transducer on one side ofthe head, positioned at the so-called temporal window. However, othertransducer configurations may be used for treating degenerative dementiawhich can provide other advantages in certain situations. For instance,using an array of transducers, the focal position may be changedelectronically, eliminating the need to physically adjust the transducerposition. As may be appreciated by one skilled in the art, thetransducer may be an annular array, which permits the focal distance tobe changed electronically by applying different time delays to eachannular element, effectively changing the radius of curvature and thusthe focal depth.

The transducer may also be configured as a phased array, and one skilledin the art would appreciate that this would permit the ultrasound beamto be steered with respect to the angle of transmission. In this case, apattern of time delays is applied across the elements, causing theultrasound beam to be steered. This may be desirable so as to insonate aregion of the brain that would otherwise require a manual angulation ofthe transducer, which may impede the transmission of ultrasound becausethe transducer lifts off the skin surface. In either case, thetransducer itself may be placed at the temporal window, since thisregion affords the least loss of energy through the skull.

Finally, a multiplicity of transducer elements may be positioned aroundthe entire skull, and the transmission from each element adjusted withregard to amplitude and phase so as to produce a focal location withinthe skull at any desired location. The adjustments compensate for therelative positions of the elements, and the attenuation and otheracoustical effects of the skull between each element and the desiredfocal location.

The so-called temporal window is known to those skilled in the art asthe region of the skull which is the thinnest and which thereforeproduces the least attenuation and other undesired effects on thetransmission of ultrasound. However, other locations can be used totransmit ultrasound to locations within the brain. For instance,ultrasound has been used to measure the position of the third ventriclewithin the brain by placing the transducer in the middle of theforehead. Although the skull is thicker there than at the temporalwindow, it is relatively uniform and thus does not induce large phasevariations in the ultrasonic signal. Thus, while there is attenuationfrom passage through the bone, the focal properties of the ultrasoundbeam are relatively stable, and thus portions of the brain in thefrontal region are readily accessible using the methods describedherein.

Hardware and Software

FIG. 13 shows a computing device 1000 used with the transducernavigation systems and performs any combination of processes discussedabove. The computing device 1000 may operate in the capacity of a serveror a client machine in a server-client network environment, or as a peermachine in a peer-to-peer (or distributed) network environment. In otherexamples, computing device 1000 may be a personal computer (PC), atablet, a Personal Digital Assistant (PDA), a cellular telephone, asmart phone, a web appliance, or any other machine or device capable ofexecuting instructions 1006 (sequential or otherwise) that specifyactions to be taken by that machine.

While only a single computing device 1000 is shown, the computing device1000 may include any collection of devices or circuitry thatindividually or jointly execute a set (or multiple sets) of instructionsto perform any one or more of the operations discussed above. Computingdevice 1000 may be part of an integrated control system or systemmanager, or may be provided as a portable electronic device configuredto interface with a networked system either locally or remotely viawireless transmission.

Processors 1004 may comprise a central processing unit (CPU), a graphicsprocessing unit (GPU), programmable logic devices, dedicated processorsystems, micro controllers, or microprocessors that may perform some orall of the operations described above. Processors 1004 may also include,but may not be limited to, an analog processor, a digital processor, amicroprocessor, multi-core processor, processor array, networkprocessor, etc.

Some of the operations described above may be implemented in softwareand other operations may be implemented in hardware. One or more of theoperations, processes, or methods described herein may be performed byan apparatus, device, or system similar to those as described herein andwith reference to the illustrated figures.

Processors 1004 may execute instructions or “code” 1006 stored in anyone of memories 1008, 1010, or 1020. The memories may store data aswell. Instructions 1006 and data can also be transmitted or receivedover a network 1014 via a network interface device 1012 utilizing anyone of a number of well-known transfer protocols.

Memories 1008, 1010, and 1020 may be integrated together with processingdevice 1000, for example RAM or FLASH memory disposed within anintegrated circuit microprocessor or the like. In other examples, thememory may comprise an independent device, such as an external diskdrive, storage array, or any other storage devices used in databasesystems. The memory and processing devices may be operatively coupledtogether, or in communication with each other, for example by an I/Oport, network connection, etc. such that the processing device may reada file stored on the memory.

Some memory may be “read only” by design (ROM) by virtue of permissionsettings, or not. Other examples of memory may include, but may be notlimited to, WORM, EPROM, EEPROM, FLASH, etc. which may be implemented insolid state semiconductor devices. Other memories may comprise movingparts, such a conventional rotating disk drive. All such memories may be“machine-readable” in that they may be readable by a processing device.

“Computer-readable storage medium” (or alternatively, “machine-readablestorage medium”) may include all of the foregoing types of memory, aswell as new technologies that may arise in the future, as long as theymay be capable of storing digital information in the nature of acomputer program or other data, at least temporarily, in such a mannerthat the stored information may be “read” by an appropriate processingdevice. The term “computer-readable” may not be limited to thehistorical usage of “computer” to imply a complete mainframe,mini-computer, desktop, wireless device, or even a laptop computer.Rather, “computer-readable” may comprise storage medium that may bereadable by a processor, processing device, or any computing system.Such media may be any available media that may be locally and/orremotely accessible by a computer or processor, and may include volatileand non-volatile media, and removable and non-removable media.

Computing device 1000 can further include a video display 1016, such asa liquid crystal display (LCD) or a cathode ray tube (CRT) and a userinterface 1018, such as a keyboard, mouse, touch screen, etc. All of thecomponents of computing device 1000 may be connected together via a bus1002 and/or network.

The system described above can use dedicated processor systems, microcontrollers, programmable logic devices, or microprocessors that performsome or all of the operations. Some of the operations described abovemay be implemented in software, such as computer readable instructionscontained on a storage media, or the same or other operations may beimplemented in hardware.

For the sake of convenience, the operations are described as variousinterconnected functional blocks or distinct software modules. This isnot necessary, however, and there may be cases where these functionalblocks or modules are equivalently aggregated into a single logicdevice, program or operation with unclear boundaries. In any event, thefunctional blocks and software modules or features of the flexibleinterface can be implemented by themselves, or in combination with otheroperations in either hardware or software.

References above have been made in detail to preferred embodiment.Examples of the preferred embodiments were illustrated in the referenceddrawings. While preferred embodiments where described, it should beunderstood that this is not intended to limit the invention to onepreferred embodiment. To the contrary, it is intended to coveralternatives, modifications, and equivalents as may be included withinthe spirit and scope of the invention as defined by the appended claims.

Having described and illustrated the principles of the invention in apreferred embodiment thereof, it should be apparent that the inventionmay be modified in arrangement and detail without departing from suchprinciples. Claim is made to all modifications and variation comingwithin the spirit and scope of the following claims.

1. A method for operating an ultrasonic transducer to treat degenerativedementia, comprising: attaching a transducer to a head of a patient;directing an ultrasonic beam from the transducer into a brain of thepatient; and focusing the ultrasonic beam at a target area of the brainto promote removal of substances that accumulate in the interstitialpathways that are at least partially responsible for the degenerativedementia.
 2. The method of claim 1, wherein the target area of the braincomprises the hippocampus and the degenerative dementia is Alzheimer'sdisease.
 3. The method of claim 1, further comprising emitting theultrasonic beam into the brain to stimulate brain tissue at a frequencythat corresponds to a naturally occurring deep sleep burst frequency ofneurons and subsequent astrocyte activation patterns that drive aconvective process that is responsible for brain solute disposal.
 4. Themethod of claim 3, wherein the bust frequency is between 1-4 Hertz. 5.The method of claim 1, further comprising applying the ultrasonic beamto the target area while the patient is sleeping to optimize soluteremoval with sonolysis caused by the interstitial spaces opening andimproved glymphatic flow during sleep.
 6. The method of claim 5, furthercomprising focusing the ultrasonic beam at the target area after thepatient has taken dexmedetomidine to block norepiphrine innervation andshrink astrocytes to open the interstitial pathways.
 7. The method ofclaim 1 further comprising applying ultrasonic beam to the target areaat a power level of around 650-10,000 milliwatts (mw) per squarecentimeter (Cm²).
 8. The method of claim 1 further comprising applyingthe ultrasonic beam to the target area to stimulate astrocyte cellfingers and produce a convective force to move fluid along theinterstitial spaces and flush out amyloid precussor proteins.
 9. Themethod of claim 1 further comprising applying the ultrasonic beam to thetarget area for around 30-90 minutes to simulate a deep sleep patientepisode.
 10. The method of claim 1, further comprising: identifying afirst target area of the brain associated with a first memorydisturbance dementia; focusing the ultrasonic beam at the first targetarea to treat the first memory disturbance dementia; identifying asecond target area of the brain associated with a second languagedisturbance dementia; and focusing the ultrasonic beam at the secondtarget area after treating the first target area to treat the secondlanguage disturbance dementia.
 11. The method of claim 1, furthercomprising focusing the ultrasonic beam at the target area of around2.5-3.5 centimeters (cm) inside of the brain.
 12. An ultrasonic devicefor treating degenerative dementia, comprising: a transducer to generatean ultrasonic beam; and a processor to control activation of thetransducer and create ultrasonic beam pulses to stimulate astrocyte cellfingers in a target area of the brain and promote the removal of amyloidprecursor proteins in interstitial spaces within the target area thatare at least partially responsible for the degenerative dementia. 13.The ultrasonic device of claim 12, wherein the processor is furtherconfigured to generate the ultrasonic beam pulses at a rate to simulatea naturally occurring deep sleep burst frequency of neurons andsubsequent astrocyte activation patterns that drive a convective processresponsible for brain solute disposal.
 14. The ultrasonic device ofclaim 12, wherein the ultrasonic beam pulse rate is between 1-4 Hertz.15. The ultrasonic device of claim 12, wherein the processor is furtherconfigured to generate a pulse train including groups of pulsesseparated by a period of between 250 milliseconds (ms) and 1000 ms. 16.The ultrasonic device of claim 15, wherein the processor is furtherconfigured to generate the pulses in the groups of pulses at a durationof between 0.2-5 ms.
 17. The ultrasonic device of claim 15, wherein theprocessor is further configured to generate a period of around 10 msbetween the pulses in the groups of pulses.
 18. The ultrasonic device ofclaim 15, wherein the processor is further configured to generate eachof the groups of pulses for a duration of around 50 ms.